: A traditionally successful approach to viral vaccines, the whole inactivated virus (WIV), has received relatively little attention in the overall effort to develop an effective HIV/AIDS vaccine. Early successes with WIV in the SIV model were confounded by xenogeneic cellular antigens derived from the human cell lines used to propagate the SIV. Growing SIV in allogeneic or autologous monkey cells has shown partial protection in some experiments. In HIV, only one inactivated virus product (the Salk/IRC Immunogen) has been tested in humans and this material is not "whole" inactivated virus since the envelope glycoprotein has been completely removed. Furthermore, this product is being tested as a therapeutic rather than a prophylactic immunogen. Since published studies of WIV using HIV-1 are extremely limited, a great deal more needs to be done to evaluate this HIV/AIDS vaccine concept. One well known technical challenge to the development of WIV is the propensity of the envelope glycoprotein of HIV-1 8gp 120) to "fall off" the virion during the process of concentration , inactivation, and purification. A second potential problem is the loss of the "native" oligomeric structure of the gp 120 during inactivation steps that involve protein denaturation (e.g. formalin). Recent studies suggest that important antigenic epitopes may be lost when gp120 is converted from oligomeric to monomeric conformation. The proposed studies will be aimed at the identification and/or selection of HIV-1 variants, representing all major subtypes (A-F), which express a phenotype of high gp 120 stability that can be maintained through multiple passages in normal peripheral blood lymphocytes or cell lines. Starting with such HIV-1 variants should provide a significant advantage in the preparation of HIV that retains full antigenicity which may be critical for protection. The applicants will assess several inactivation procedures that preferentially target nucleic acid rather than protein (e.g. psoralen-UV, beta-propiolactone, gamma irradiation), oligomeric conformation of gp120. Finally, they will assess the immunogenicity of several WIV preparations in small animals. Initial studies will focus on subtype-C, one of the most prevalent subtypes in developing countries.